Erythromycin A is an antibiotic clinically widely used as an agent for treating infectious diseases caused by Gram-positive bacteria, mycoplasmas, etc. However, erythromycin A is decomposed by the gastric acid due to instability to acids, and thereby has a drawback of no constancy of movement in the body. Hitherto many erythromycin A derivatives have been prepared for the purpose of the improvement of the biological or pharmacological properties. For example, it is reported that 6-O-methylerythromycin A derivatives have an improved stability to acids and have a superior in vivo antibacterial activity in comparison with erythromycin A when administered orally (U.S. Pat. No. 4,331,803). Recently, it is also reported that 11,12-cyclic carbamate derivatives are prepared with the aim of expansion of antibacterial spectrum as well as stability to acids (EP. patent. No. 487411, U.S. Pat. No. 4,742,049, EP. Patent No. 676409 and ibid. 638584).
An object of the present invention is to provide a novel antibiotic erythromycin A derivative or a salt thereof having a strong antibacterial activity against not only known erythromycin-sensitive bacteria but also Haemophilus influenzae and erythromycin-resistant bacteria which recently are showing a tendency to increase, and a composition comprising the same as an effective component. Other objects of the present invention are to provide a method for the treatment of a bacterially infectious disease which comprises administering a pharmaceutically effective amount of the above-mentioned erythromycin A derivative or salt thereof to a patient, and use of the above-mentioned erythromycin A derivative or salt thereof for the treatment of a bacterially infectious disease.
The present inventors have variously researched on erythromycin A derivatives, in particular, their 11,12-cyclic carbamate compounds which have a certain substituted amino group on the nitrogen atom of the carbamate group at the 11-position, a methoxy group at the 6-position and a carbonyl group at the 3-position. As a result, compounds having the benzyl group substituted by an alkyl group, an alkoxy group (particularly, a methoxy group) or an amino group on the benzene ring have been found to have a stronger antibacterial activity against erythromycin-resistant bacteria than the compounds of which substituent on the nitrogen atom forming the carbamate group at the 11-position is a 2-(N-benzyl-N-methylamino)ethyl group (EP Patent No. 487411), and compounds having a pyridylmethyl group or a quinolylmethyl group other than the benzyl group have also been found to similarly have a strong activity. The present invention has been accomplished on the basis of the finds.
The present invention relates to an erythromycin A derivative represented by Formula (I): ##STR2## (wherein n is an integer of 2 to 4, R.sup.1 is a pyridylmethyl group, a furylmethyl group, a thienylmethyl group, a quinolylmethyl group or a benzyl group having 1 to 3 substituents selected from the group consisting of an alkyl group having 1 to 5 carbon atoms, a nitro group, an alkoxy group having 1 to 5 carbon atoms, an amino group and an amino group substituted by 1 or 2 alkyl groups having 1 to 5 carbon atoms, R.sup.2 is the same group as defined for R.sup.1, a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an acetyl group or a pyridylacetyl group, and R.sup.3 is an alkyl group having 1 to 5 carbon atoms or a cinnamyl group) or a pharmaceutically acceptable salt thereof.
In the above-mentioned formula, n is preferably 2 or 3. The alkyl group having 1 to 5 carbon atoms in the definition for R.sup.1 refers to a straight or branched alkyl group, and is preferably a methyl group. The alkoxy group having 1 to 5 carbon atoms refers to a straight or branched alkoxy group, and is preferably a methoxy group, and the amino group substituted by 1 or 2 alkyl groups having 1 to 5 carbon atoms is preferably a dimethylamino group. The alkyl group having 1 to 5 carbon atoms in the definition for R.sup.2 refers to a straight or branched alkyl group, and is preferably a methyl group, an ethyl group or a propyl group. The alkyl group having 1 to 5 carbon atoms in the definition for R.sup.3 refers to a straight or branched alkyl group, and is preferably a methyl group.
The pharmaceutically acceptable salt refers to a salt used in chemotherapy or prophylaxis of bacterially infectious diseases, for example, a salt with acetic acid, propionic acid, butyric acid, formic acid, trifluoroacetic acid, maleic acid, tartaric acid, citric acid, stearic acid, succinic acid, ethylsuccinic acid, lactobionic acid, gluconic acid, glucoheptonic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, laurylsulfuric acid, malic acid, aspartic acid, glutaminic acid, adipic acid, cysteine, N-acetylcysteine, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, hydroiodic acid, nicotinic acid, oxalic acid, picric acid, thiocyanic acid, undecanoic acid, polyacrylate or carboxyvinyl polymer.
The compounds of the present invention can be prepared, for example, as follows. ##STR3##
Step (1); 10,11-Anhydro-2',4"-di-O-acetyl-12-O-imidazolylcarbonyl-6-O-methylerythrom ycin A described in EP patent No. 638584 is reacted with a diamine such as ethylenediamine or 1,3-diaminopropane in a suitable solvent at a temperature of from -30.degree. C. to 100.degree. C., preferably 0.degree. C. to 30.degree. C. The resulting 11,12-cyclic carbamate compound is reacted in a lower alcohol or an aqueous lower alcohol, if desired, in the presence of a base such as sodium bicarbonate, at a temperature of from 0.degree. C. to 100.degree. C., preferably room temperature to 80.degree. C. to remove the protective group at the 2'-position, thereby there is obtained Compound (a) (wherein n is as defined above). Examples of the suitable solvent to be used herein are acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dioxane, ethyl acetate, N-methylpyrrolidone, an aqueous solution thereof and a mixture thereof. Examples of the lower alcohol to be used herein include methanol, ethanol and propyl alcohol.
Step (2-I); Compound (a) is reacted with quinolylaldehyde, furaldehyde, thiophenecarboxaldehyde, pyridylaldehyde or a substituted benzaldehyde in a slightly excess amount relative to Compound (a) and a reductant in a lower alcohol in the presence of an acid such as acetic acid at a temperature of from -30.degree. C. to 100.degree. C., preferably 0.degree. C. to 60.degree. C. to give Compound (b) (wherein n and R.sup.1 are as defined above). The lower alcohol is the same as used in Step (1). Examples of the reductant to be used herein are sodium borohydride, sodium cyanoborohydride and sodium triacetoxyborohydride.
Step (2-II); Compound (b) is reacted using formaldehyde, acetaldehyde, quinolylaldehyde, furaldehyde, thiophenecarboxaldehyde or pyridylaldehyde in the same manner as in Step (2-I) to give Compound (c) (wherein n, R.sup.1 and R.sup.2 are as defined above).
Step (3); Compound (c) is reacted with an acid to give Compound (d) (wherein n, R.sup.1 and R.sup.2 are as defined above). Examples of the acid are hydrochloric acid, hydrobromic acid and sulfuric acid, preferably 0.5 to 2 N hydrochloric acid, and if desired, a mixture of the acid with a lower alcohol such as methanol or ethanol.
Step (4); Compound (d) is reacted with acetic anhydride or acetyl halide in an inert solvent to give a compound which is protected with an acetyl group at the 2'-position. Examples of the inert solvent to be used are dichloromethane, dichloroethane and acetone.
Step (5); The compound obtained in Step (4) is oxidized in an inert solvent using chromic acid, chromic acid-pyridine, pyridinium chlorochromate, pyridinium dichromate or an activated dimethyl sulfoxide at a temperature of from -78.degree. C. to 30.degree. C., and then the resulting 3-ketone derivative is oxidized in a lower alcohol or an aqueous lower alcohol, (herein, a base such as sodium bicarbonate may be added), at a temperature of from 0 .degree. C. to 100.degree. C., preferably room temperature to 30 .degree. C., followed by removal of the protective group at the 2'-position to give a compound of the present invention represented by Compound (e) (wherein n, R.sup.1 and R.sup.2 are as defined above). The inert solvent is the same as used in Step (4). Examples of the activating agent of dimethyl sulfoxide are acetic anhydride, trifluoroacetic anhydride, oxalyl chloride, phosphorus pentachloride, pyridinium sulfate, pyridinium trifluoroacetate, 1,3-dicyclohexylcarbodiimide and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The lower alcohol is the same as used in Step (1).
The compounds of the present invention can be administered orally or parenterally in the various preparation forms for the purpose of the application based on the pharmacological properties. The pharmaceutical composition of the present invention can be prepared by homogeneously mixing an effective amount of the compound of the present invention in the free form or in the form of an acid addition salt thereof, with a pharmaceutically acceptable carrier, which may be various forms according to the desired preparation forms. Examples of the preparation forms in the present invention are tablets, capsules, powders, troches, ointments, suspensions, suppositories and injections, all of which can be prepared according to conventional preparation techniques. The dose for treating an adult is from 100 to 1000 mg/day in 2 or 3 divided doses. This dose can be increased or decreased depending on the age, body weight and conditions of the patient.